MUCOCILIARY TRANSPORT--INHIBITORY NEURAL REGULATION

粘膜纤毛运输——抑制性神经调节

• 批准号: 6489859
• 负责人: Donovan B Yeates
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489859
• 关键词: C fiber; active transport; biological fluid transport; bronchial mucus; dogs; hexamethonium compound; homeostasis; irritation /irritant; neural inhibition; neuropharmacology; neuroregulation; pulmonary respiration; pulmonary stretch receptors; respiratory airway clearance; respiratory epithelium; respiratory pharmacology; respiratory reflex; secretion; stretch reflex; sulfur oxides; vagus nerve

DESCRIPTION (Applicant's abstract): We have discovered novel inhibitory neural pathways which interact with excitatory neural reflexes to regulate tracheobronchial mucociliary function. We propose that impaired tracheobronchial mucociliary clearance results from activation of predominantly inhibitory reflexes. These neural reflexes, activated by ammonia and SO2 regulate the components of the mucociliary transport system, namely ciliary beat frequency and airway secretory output. Inhalation of acidic irritants, such as SO2, primarily activate inhibitory neural pathways that suppress ciliary activity yet via cause a highly viscous mucus with an large relaxation time. In concert, these responses result in defective mucociliary transport and mucus accumulation in the airways. To delineate the proposed inhibitory neural pathways and their roles in the regulation of the mucociliary transport system, we will use a canine model in which the vagosympathetic trunks are exteriorized in skin tubes. Tracheal mucus velocity, TMV, and bronchial mucociliary clearance, BMC, will be measured using radioaerosol techniques. Airway secretory output, ASO, will be measured using a secretion collecting endotracheal tube and the rheological properties measured using rotational magnetic microrheometry. Ciliary beat frequency, CBF, will be measured in the trachea using heterodyne laser light scattering. SO2 will be used to activate the inhibitory reflex. We will demonstrate two inhibitory reflexes, one that traverses the vagosympathetic trunks and the other the sympathetic ganglia. We will identify the dominant ganglionic and efferent inhibitory and excitatory neural transmitters by cooling the vagosympathetic trunks to 0 degrees C, and by judicious local administration of general and specific inhibitors of ganglionic and receptor function. We will show the causal relationships between the neural transmission of the proposed inhibitory reflexes, and the suppression of CBF, changes in ASO and mucus viscosity and relaxation time. Through the derivation of the airway fluid depth, AFD, and the distance mucus is transported/ciliary beat, we will show the extent to which changes in CBF and/or airway secretory output and viscosity and relaxation time contribute to impaired mucociliary transport. Through the elucidation of the neural regulation of normal mucociliary function and the mechanisms underlying perturbations in this regulation that lead to abnormal mucociliary clearance, we will ascertain new potential pathogenic mechanisms contributing to the pathogenesis of diseases of the airways such as bronchitis, asthma and cystic fibrosis. Also possible sites and agents for therapeutic intervention will be identified.

描述（申请人的摘要）： 我们发现了与之相互作用的新型抑制性神经途径 兴奋性神经反射，以调节气管粘膜胶囊 功能。我们建议那些受损的气管粘膜胶体纤毛 清除率主要是激活主要抑制性反射。 这些神经反射，由氨和SO2激活 粘膜运输系统的组件，即睫状节 频率和气道分泌输出。吸入酸性刺激物， 例如SO2，主要激活抑制抑制性神经途径 纤毛活动，但通过引起高度粘性的粘液 放松时间。在共同的情况下，这些反应导致有缺陷 气道中的粘膜屈液和粘液积聚。到 描述提出的抑制性神经途径及其在 粘膜循环系统的调节，我们将使用犬 在皮肤中外部对流浪性交响的树干进行外部的模型 管。气管粘液速度，TMV和支气管粘膜固定 清除率BMC将使用放射性化学技术进行测量。呼吸道 分泌输出ASO将使用分泌收集来测量 气管管和使用的流变特性 旋转磁性微型计量计。睫状节拍频率，CBF，将 使用异差激光散射在气管中测量。 SO2 将用于激活抑制反射。我们将展示两个 抑制性反射，一种遍历迷人交感的树干和 另一个是同情的神经节。我们将确定占主导地位 神经节和传出抑制和兴奋性神经发射器 通过将流浪性的树干冷却至0度C，并通过明智 神经节的一般和特定抑制剂的地方给药 和受体功能。我们将展示 拟议的抑制反射的神经传播， 抑制CBF，ASO和粘液粘度的变化以及放松 时间。通过气道流体深度，AFD和 距离粘液被运输/睫状节拍，我们将显示 哪些在CBF和/或气道分泌产出和粘度以及 放松时间会导致粘膜纤毛运输受损。通过 阐明正常粘毛功能的神经调节 以及该法规中的扰动的基础机制 为了异常的粘膜纤毛清除，我们将确定新的潜力 病原机制有助于疾病的发病机理 气道，例如支气管炎，哮喘和囊性纤维化。还 治疗干预的可能地点和代理将是 确定。